Emesis treatment

ABSTRACT

A composition for the treatment of emesis comprising 8-hydroxy-2-(dipropylamino)tetralin in which the ratio of the S enantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the R enantiomer of the 8-hydroxy-2-(dipropylamino)tetralin is between 2:1 and 10:1, and a method of treating or preventing emesis with such a composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/894,724, filed on Feb. 12, 2018 and entitled EMESIS TREATMENT, whichis a continuation of U.S. patent application Ser. No. 14/447,518, filedon Jul. 30, 2014, which is a continuation of U.S. patent applicationSer. No. 13/501,531 filed on Apr. 12, 2012, which is the U.S. nationalstage of International Patent Application No. PCT/US2010/052961 filed onOct. 15, 2010, which claims the benefit of priority from U.S. PatentApplication No. 61/252,291, filed Oct. 16, 2009 and entitled TREATMENTAND PREVENTION OF EMESIS. The present application claims the benefit ofpriority under 35 U.S.C. § 120 from the foregoing applications, and thedisclosures of the foregoing applications are incorporated herein byreference in their entirety.

BACKGROUND

Emesis (vomiting) is a common symptom of a variety of disorders, broughton by events including the administration of chemotherapeutic agents,motion, pregnancy (morning sickness), and infections. Anti-emetictherapy generally involves removing the offending stimulus or resolvingthe condition responsible for the emesis. There are only a limitednumber of medicinal remedies currently available for emesis, and theseoften have undesired side effects, such as sedation or anxiety.

The use of (±)-8-Hydroxy-2-(dipropylamino)tetralin [(±)-8-OH-DPAT] hasbeen reported for the treatment of emesis (see, e.g., U.S. Pat. No.4,943,428). The administration of racemic 8-OH-DPAT, however, has beenfound to cause anxiety in test subjects. Racemic 8-OH-DPAT therefore hasnot been developed for the treatment or prevention of emesis.

SUMMARY

There remains therefore a need for improved treatments for emesis, inparticular treatments with improved side effect profiles. The presentcompositions for the treatment of emesis in mammals, which arenon-sedating and have reduced anxiogenic effects, meet this need.

In one embodiment, the present method for the treatment of emesis in amammal, such as a human, comprises the step of administering to themammal a composition comprising S(−)-8-hydroxy-2-(dipropylamino)tetralinand R(+)-8-hydroxy-2-(dipropylamino)tetralin, wherein one of theS(−)-8-hydroxy-2-(dipropylamino)tetralin or theR(+)-8-hydroxy-2-(dipropylamino)tetralin is present in the compositionin a greater amount. The type of emesis treated can be, for example,delayed emesis or anticipatory emesis. Such emesis can be associatedwith pregnancy, migraine headache, motion, exposure to chemical agents,exposure to radiation, viral infection, bacterial infection, orconditions or events associated with emesis.

In the present methods, the amount ofS(−)-8-hydroxy-2-(dipropylamino)tetralin in the composition ispreferably greater than the amount ofR(+)-8-hydroxy-2-(dipropylamino)tetralin in the composition used fortreatment. For example, the ratio ofS(−)-8-Hydroxy-2-(dipropylamino)tetralin toR(+)-8-Hydroxy-2-(dipropylamino)tetralin present in the composition isat least 2:1, and more preferably is at least 8:1. The amount ofS(−)-8-Hydroxy-2-(dipropylamino)tetralin administered can be at least0.08 mg/kg, for example, such as between 0.08 mg/kg and 0.16 mg/kg, andthe amount of R(+)-8-Hydroxy-2-(dipropylamino)tetralin administered ispreferably less than 0.04 mg/kg.

In a particular embodiment, the present method for the treatment ofemesis in a human or other mammal comprises administering to the mammala composition comprising a mixture of S and R enantiomers of a2-aminotetralin compound having the following formula:

wherein:

-   -   R₁ and R₂ are each, independently, selected from the group        consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkenyl, or        alternately, R₁ and R₂ can be taken together with the nitrogen        to which they are attached to form a 5- to 8-membered        nitrocyclic ring, wherein the alkyl, alkenyl, and nitrocyclic        groups are unsubstituted, or can be substituted with one or more        halide atoms.    -   R₃ is selected from the group consisting of OH, F, NH₂, CH₃, and        SH;    -   R₄ and R₅ are each, independently, selected from the group        consisting of hydrogen, halide, OH, CF₃, C₁-C₈ alkyl, and C₁-C₈        alkenyl, COR₆, and OR₆, wherein the alkyl and alkenyl groups are        unsubstituted, or can be substituted with one or more halide        atoms, and wherein R₄ and R₄ are each, independently substituted        at the 1-, 3-, 4-, 5-, 6-, and 7-ring positions of the tetralin        ring structure;    -   R₆ is selected from the group consisting of hydrogen, C₁-C₅        alkyl, C₁-C₅ alkenyl, and aminoalkyl, and    -   wherein the composition comprises an excess amount of one of the        S or R enantiomers of the compound of formula I.

In a particular embodiment, R₁ and R₂ are each independently C₁-C₈alkyl, such as n-propyl; R₃ is OH; and R₄ and R₅ are each independentlyhydrogen, and the composition comprises an excess amount of the Senantiomer of the compound.

The present method for the treatment of emesis in a mammal can furthercomprise administering to a mammal a composition comprising a mixture ofan S enantiomers of a 2-aminotetralin compound and an R enantiomer of a2-aminotetralin compound, where the composition comprises an excessamount of at least one of the S enantiomer of the 2-aminotetralincompound or the R enantiomer of the 2-(amino) tetralin compound, and atleast one of the S enantiomer of the 2-aminotetralin compound or the Renantiomer of the 2-(amino) tetralin compound has activity as a5-HT_(1A) agonist. The 2-aminotetralin compound in this embodiment canbe (±)-8-hydroxy-2-(dipropylamino)tetralin, and the S enantiomer of the8-hydroxy-2-(dipropylamino)tetralin can be present in the composition inan amount greater than the R enantiomer of the8-hydroxy-2-(dipropylamino)tetralin.

The present invention further comprises a pharmaceutical compositioncomprising 8-hydroxy-2-(dipropylamino)tetralin in which the ratio of theS enantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the Renantiomer of the 8-hydroxy-2-(dipropylamino)tetralin can be between 2:1and 10:1, and is more preferably between 4:1 and 8:1, and mostpreferably is about 8:1.

FIGURES

FIG. 1 is a bar graph showing the amount of protection from vomitingprovided by 8-OH-DPAT compositions in female cats in a model of emesisinduced by xylazine.

FIG. 2 is a graph representing the binding affinity of racemic 8-OH-DPATat the 5-HT_(1A) human receptor ligand.

FIG. 3 is a graph representing the functional activity of racemic8-OH-DPAT at the 5-HT_(1A) human receptor ligand, showing the agonistresponse of racemic 8-OH-DPAT (as a percent of the response of a knownagonist of 5-HT_(1A)) versus the log of the molar concentration ofracemic 8-OH-DPAT.

FIG. 4 is a graph representing the functional activity of R(+)-8-OH-DPATat the 5-HT_(1A) human receptor ligand, showing the agonist response ofR(+)-8-OH-DPAT (as a percent of the response of a known agonist of5-HT_(1A)) versus the log of the molar concentration of R(+)-8-OH-DPAT.

FIG. 5 is a graph representing the binding affinity of S(−)-8-OH-DPAT atthe 5-HT_(1A) human receptor ligand, showing the agonist response ofS(−)-8-OH-DPAT (as a percent of the response of a known agonist of5-HT_(1A)) versus the log of the molar concentration of S(−)-8-OH-DPAT.

FIG. 6 is a bar graph showing the amount of protection from vomitingprovided by the present 8-OH-DPAT compositions at varying dosages inmale shrews in a model of emesis induced by motion.

FIG. 7 is a bar graph showing the amount of protection from vomitingprovided by the present 8-OH-DPAT compositions at varying dosages infemale shrews in a model of emesis induced by nicotine tartarate.

FIG. 8 is a bar graph showing the amount of protection from vomitingprovided by the present 8-OH-DPAT compositions at varying dosages infemale shrews in a model of emesis induced by cisplatin.

DESCRIPTION

The present methods for treating emesis and/or nausea in a mammalcomprise administering to the mammal a composition comprising a mixtureof an effective dosage of a 2-aminotetralin compound, where one of the Sor R enantiomers of the 2-aminotetralin compound is present in thecomposition in excess of the other enantiomer. The composition iseffective in treating emesis with a reduced side effect profile comparedto current therapeutic agents.

Definitions

As used herein, the following terms and variations thereof have themeanings given below, unless a different meaning is clearly intended bythe context in which such term is used.

“About” when used in reference to a numerical value means plus or minusten percent of the indicated amount. For example and not by way oflimitation, “about 10” means between 9 and 11, and “about 10%” meansbetween 9% and 11%.

“2-aminotetralin” refers to a 1,2,3,4-tetrahydronaphthalene, substitutedin the 2-position with an amino group (—NR₁R₂), as shown below, with thepositions in the tetralin ring system also designated below.

“8-(OH)-DPAT” is (±)-8-Hydroxy-2-(dipropylamino)tetralin.

“Anticipatory emesis” refers to a conditioned vomiting response, i.e.emesis that occurs in a subject before the subject is exposed to asubstance, agent, or event (such as exposure to a chemotherapeuticagent) which has previously caused the subject to experience emesis.

“Anxiety” refers to a sense of apprehension and fear often marked byphysical symptoms (such as sweating, tension, and increased heart rate).Anxiety can be measured in clinical and preclinical models known tothose of skill in the art.

“Anxiogenic” describes a substance, agent, event, or condition thatcauses anxiety.

“Delayed emesis” means emesis that occurs in a subject more than 24hours after the subject is exposed to a substance, agent, or event whichresults in the subject experiencing emesis, or that occurs more than 24hours after the subject contracts a condition which results in thesubject experiencing emesis.

“Emesis” refers to vomiting, i.e., the reflex act of ejecting thecontents of the stomach through the mouth.

“Enantiomer” means a compound that is one of two stereoisomers that arenonsuperimposable complete mirror images of each other.

“Enantiomeric excess” describes a composition in which one enantiomer ispresent in an amount which exceeds the amount of the other entantiomerin the composition, and is defined as the absolute difference betweenthe mole fraction of each enantiomer. This can be expressedformulaically as follows:

ee=|F ₊ −F ⁻|

where

F ₊ +F ⁻=1.

“Nausea” refers to a sensation of unease and discomfort in the stomachaccompanied by an urge to vomit. Nausea can be measured in ways known tothe art, such as through the use of a visual analog scale (VAS).

“Percent enantiomeric excess” means the enantiomeric excess expressed asa percentage. For example, a sample with 70% of S isomer and 30% of Rwill have an enantiomeric excess of 40%. This can also be thought of asa mixture of 40% pure S with 60% of a racemic mixture (which contributes30% R and 30% S to the overall composition).

“Treatment,” in the context of treating emesis by administering one ofthe compositions disclosed herein, includes both prophylactic treatmentand the treatment of emesis after a subject experiences emesis.Prophylactic treatment includes administration of a composition before asubject experiences emesis, such as when the subject experiences nausea,as well as administration of the composition before the subject isexposed to a substance, agent, or event, or before the subject contractsa condition, which results in or is likely to result in the subjectexperiencing emesis.

As used herein, the term “comprise” and variations of the term, such as“comprising” and “comprises,” are not intended to exclude otheradditives, components, integers or steps. The terms “a,” “an,” and “the”and similar referents used herein are to be construed to cover both thesingular and the plural unless their usage in context indicatesotherwise.

2-Aminotetralin Compounds

The present compositions comprise improved mixtures of the S and Renantiomers of a 2-aminotetralin compound of formula I:

wherein:

-   -   R₁ and R₂ are each, independently, selected from the group        consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkenyl, or        alternately, R₁ and R₂ can be taken together with the nitrogen        to which they are attached to form a 5- to 8-membered        nitrocyclic ring, wherein the alkyl, alkenyl, and nitrocyclic        groups are unsubstituted, or can be substituted with one or more        halide atoms;    -   R₃ is selected from the group consisting of OH, F, NH₂, CH₃, and        SH;    -   R₄ and R₅ are each, independently, selected from the group        consisting of hydrogen, halide, OH, CF₃, C₁-C₈ alkyl, and C₁-C₈        alkenyl, COR₆, and OR₆, wherein the alkyl and alkenyl groups are        unsubstituted, or can be substituted with one or more halide        atoms, and wherein R₄ and R₄ are each, independently substituted        at the 1-, 3-, 4-, 5-, 6-, and 7-ring positions of the tetralin        ring structure; and

R₆ is selected from the group consisting of hydrogen, C₁-C₅ alkyl, C₁-C₅alkenyl, and aminoalkyl.

In a preferred embodiment, R₁ and R₂ are each independently C₁-C₈ alkyl;R₃ is OH; and R₄ and R₅ are each independently hydrogen. R₁ and R₂ canfor example, each independently be n-propyl.

In a further preferred embodiment, the 2-aminotetralin compound is acompound of formula II:

wherein the R₁, R₂, R₃, R₄ and R₅ groups are as described above for the2-aminotetralin compound of formula I. In a particularly preferredembodiment, the 2-aminotetralin is 8-(OH)-DPAT.

2-Aminotetralin Compositions

The present compositions comprise a compound according to formula I,such as 8-OH-DPAT, in which there exists an enantiomeric excess of oneof the S or R enantiomers of the compound. Preferably, the S enantiomerof a 2-aminotetralin compound (an “S-2-aminotetralin” compound) is inexcess of the R enantiomer of the 2-aminotetralin compound (an“R-2-aminotetralin” compound), and such excess is a percent enantiomericexcess of at least about 50%, preferably at least 60%, and morepreferably at least 80%. The ratio of S- to R-enantiomers used in thepresent compositions is preferably at least than 2:1, more preferably atleast 4:1, and even more preferably at least 8:1, for example 10:1.Preferably, the ratio of the S-2-aminotetralin compound to theR-2-aminotetralin compound is an amount effective to prevent emesiswithout producing an anxiogenic effect.

Emesis can be treated by administering one or more of the presentcompositions, preferably including pharmaceutically acceptableexcipients, to a mammal such as a human. The present compounds arebeneficial in the treatment of acute, delayed or anticipatory emesis,including emesis induced by chemotherapy, radiation, toxins, viral orbacterial infections, pregnancy, vestibular disorders (e.g. motionsickness, vertigo, dizziness and Meniere's disease), surgery, migraine,and variations in intracranial pressure. The use of the presentcompositions is also of benefit in the therapy of emesis induced byradiation, for example during the treatment of cancer, and in thetreatment of post-operative nausea and vomiting. The use of the presentcompositions is also beneficial in the therapy of emesis induced byantineoplastic (cytotoxic) agents including those routinely used incancer chemotherapy, and emesis induced by other pharmacological agents.Further, the present compositions can also be used in the therapy ofacute, delayed or anticipatory emesis from an unknown cause. In additionto treating emesis, the present compositions can be used to treatnausea.

8-OH-DPAT Compositions

In one embodiment, the present compositions comprise non-racemicmixtures of 8-OH-DPAT enantiomers. We have found that the R-enantiomerof 8-OH-DPAT, administered alone, is 100% effective in preventingchemically-induced emesis, but has a moderate to strong anxiety-inducingeffect when administered to test subjects. We have further discoveredthat the S-enantiomer of 8-OH-DPAT, although not fully effective inpreventing chemically induced emesis when administered as a sole agent,induces no anxiety or only slight anxiety in test subjects. By alteringthe ratios of the R- and S-enantiomers in a mixture of 8-OH-DPATenantiomers, therefore, the present inventors have produced acomposition with improved properties. A specific combination of the S(−)and R(+) isomers of 8-OH-DPAT can be used in the treatment of emesis ina mammal, preferably a human, without anxiogenic effects.

This conclusion is illustrated in FIG. 1, which shows data gathered froma test of female domestic short-haired felines which were subcutaneously(SC) administered either:

(i) 0.9% sodium chloride vehicle (n=6);

(ii) 0.16 mg/kg of (±)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide(n=6);

(iii) 0.08 mg/kg R(+)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide(n=6); or

(iv) 0.08 mg/kg S(−)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide(n=5).

Fifteen minutes later, 0.66 mg/kg xylazine was administeredsubcutaneously, and the test subjects where then observed for 30minutes. As shown in the first bar of FIG. 1, when the 0.9% sodiumchloride vehicle was administered to the cats, all the cats vomited,exhibiting 0% protection against xylazine-induced emesis, and none ofthe cats showed any anxiety 15 minutes after treatment with the vehicle.When the racemic mixture of (±)-8-Hydroxy-2-(dipropylamino)tetralinhydrobromide was administered to the cats, none of the cats vomited,exhibiting 100% protection against xylazine-induced emesis, but the catsshowed a moderate level of anxiety 15 minutes after treatment (secondbar of FIG. 1). As shown in the third bar of FIG. 1, whenR(+)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide was administeredto the cats as a sole agent, none of the cats vomited, but the catsshowed an extreme level of anxiety 15 minutes after treatment. Bycontrast, when S(−)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide wasadministered to the cats, 40% of cats vomited, exhibiting 60% protectionagainst xylazine-induced emesis, and the cats did not show any anxiety15 minutes after treatment (fourth bar of FIG. 1). Accordingly, aspecific combination of the S(−) and R(+) isomers of a 2-aminotetralincompound has been found to be useful for the treatment of emesis in amammal without an anxiogenic effect.

Further testing revealed that an excess of the S-enantiomer of 8-OH-DPATcan produce a composition which blocks emesis without producing anxiety.The ratio of S- to R-enantiomers used in the present 8-OH-DPATcompositions is preferably at least greater than 2:1, and morepreferably at least 4:1. A particularly preferred ratio of S- toR-8-(OH)-DPAT is an eight to one (8:1) excess of S(−) 8-OH-DPAT, whichhas been found to provide complete protection against emesis and noanxiety in test subjects. When administered to test subjects, the amountof S(−)-8-(OH)-DPAT administered is preferably at least 0.08 mg/kg, andmore preferably between 0.08 mg/kg and 0.16 mg/kg. The amount ofR(+)-8-(OH)-DPAT administered in such compositions is also preferablyless than 0.04 mg/kg.

When mixtures of non-racemic 8-(OH)-DPAT of the present invention areadministered to a subject, such as compositions comprising ratios ofS-8-(OH)-DPAT to R-8-(OH)-DPAT of 2:1, 4:1, 8:1 or more, suchcompositions are preferably administered in amounts of at least 0.01mg/kg, more preferably of at least 0.02 mg/kg, 0.03 mg/kg, or 0.05mg/kg, and even more preferably of at least 0.08 mg/kg. The foregoingdosing is appropriate, in particular, for motion-induced emesis andemesis resulting from some chemical stimuli. For other chemicals or someenvironmental triggers for emesis, such as radiation, more potent dosesof the present compositions may be required, for example at least 0.2mg/kg, 0.3 mg/kg, 0.5 mg/kg, or 0.8 mg/kg or greater. One of skill inthe art can determine an appropriate dose for a particular subject.

The present 8-OH-DPAT compositions therefore comprise amounts of theR-enantiomer of 8-OH-DPAT which are sufficient to substantially orcompletely block emesis in mammals, but which do not produce the anxietyassociated with racemic mixtures of 8-OH-DPAT. Without being bound to aparticular theory, the inventors believe that the S-enantiomer of8-OH-DPAT blocks the anxiogenic effects of racemic 8-OH-DPAT, inparticular of the R-enantiomer of 8-OH-DPAT. Accordingly, by varying theratio of the S- to R-enantiomers of 8-(OH)-DPAT, preferably so as toproduce an excess of the S-enantiomer, both an anti-emetic and ananti-anxiogenic effect can be achieved.

Previous findings suggest that R(+)-8-OH-DPAT is a full agonist of the5-HT_(1A) receptor and that S(−)-8-OH-DPAT is a partial agonist at the5-HT_(1A) receptor. (See, e.g., Cornfield L. et al., Mol. Pharmacol.,1991, 39, 780; Hadrava V. et al., J Psychiatry Neurosci., 1996, 21(2),101-8; and Dabrowska J. et al., Biochem. Pharmacol., 2006, 72, 498-511).Contrary to these findings, in which both R(+)-8-OH-DPAT andS(−)-8-OH-DPAT underwent cellular functional assays using the rat ligandof the 5-HT_(1A) receptor, both R(+)-8-OH-DPAT and S(−)-8-OH-DPAT arefull agonists of the 5-HT_(1A) human receptor ligand.

The invention can be appreciated in certain aspects with reference tothe following examples, offered by way of illustration, not by way oflimitation. Materials, reagents and the like to which reference is madein the following examples are obtainable from commercial sources, unlessotherwise noted.

EXAMPLES Example 1: Blocking Xylazine-Induced Emesis I. AnimalPreparation

A. Quarantine:

Upon arrival the animals were examined to ensure that they were healthyand were quarantined for at least seven days before placement on study.At the end of the quarantine period, the general health of the animalswas examined. Any unhealthy animals were not used in the study.

B. Food and Housing:

The animals were housed in individual hanging stainless steel cages.They received Laboratory Feline Diet 5003 (available from Purina Mills,LLC, Gray Summit, Mo.). The animals were provided tap water ad libitum.

II. Experimental Procedure

A. Fasting:

Animals had free access to food and water until the time of testing.

B. Motion Screening and Testing:

1. A motion stimulus was provided by a “felis wheel”, a motor-drivendevice that resembles an amusement park Ferris wheel. The cats rode inclear plastic boxes suspended from two 0.445 m arms that rotated aboutthe central horizontal axis at 0.28 Hz (17 rpm). Motion tests lasted for30 minutes of rotation followed by one minute of observation at rest.

2. Animals were screened for motion sickness susceptibility by beingtested through the felis wheel three times. Those cats that becameadequately motion sick (i.e. vomited) on at least two out of three testswere considered adequately susceptible for motion testing.

3. For the evaluation of test compounds against motion sickness inducedemesis, cats susceptible to motion sickness were initially injectedsubcutaneously with a freshly prepared solution of test compound in 0.9%sodium chloride or vehicle (injection volume of 0.1 ml/kg) 15 minutesprior to felis wheel exposure.

4. Vehicle or test compound evaluation in motion sickness inducedemesis: After the 15 minute subcutaneous pretreatment with eithervehicle or test compound animals rode in clear plastic boxes suspendedfrom two 0.445 m arms that rotated about the central horizontal axis at0.28 Hz (17 rpm). Observation took place during the motion tests thatlast for 30 minutes of rotation followed by an additional one minute ofobservation at rest. Behavioral scoring was completed using the vomitscale.

III. Xylazine-Induced Emesis

Cats not susceptible to motion sickness were assigned to the xylazinetesting group. Xylazine stimulates receptors on a pathway different fromthat used by motion sickness and thus served as a test of the generalityof anti-emetic effects observed with motion testing.

Prior to the evaluation of anti-emetic compounds, the production of anemetic response by xylazine in felines was confirmed in the laboratory.Cats were injected subcutaneously with either a freshly preparedsolution of 0.66 mg/kg of xylazine in 0.9% sodium chloride or 0.9%sodium chloride vehicle, both adjusted to an injection volume of 0.1ml/kg.

One week following the confirmation of an emetic response by the cats,subject cats were given either vehicle or test compound/composition in0.9% sodium chloride or vehicle (injection volume of 0.1 ml/kg)subcutaneously, 20 minutes before administration of xylazine. Cats wereobserved for 30 minutes following xylazine treatment or for 15 minutesafter the last emetic episode, whichever occurred later. Animals werescored using the vomit scale developed by Suri et al., 1979. Additionalexperiments were separated by at least a 1 week washout period.

IV. Data Collection

A. Vomit Scale Scoring:

-   -   1. Sal I (licking—parasympathetic): 1 pt    -   2. Sal II (drool, thin/frothy—early sympathetic): 2 pts    -   3. Sal III (stringy saliva, dangles—sympathetic): 4 pts    -   4. Defection: 8 pts    -   5. Urination: 8 pts    -   6. Wretch/vomiting: 16 pts

B. Defensive Behavior Scale:

-   -   1. No defensiveness: normal behavior;    -   2. Slight defensiveness: retreating to the rear of the cage when        approached and/or growling when being carried;    -   3. Moderate defensiveness: exhibiting flattened ears and trying        to claw and bite when being carried;    -   4. Strong defensiveness: vigorous clawing and biting to prevent        being handled.

V. Statistical Methods

Dose response curves were analyzed by Cochran's Q-test to establishsignificant effects. Paired comparisons were made using McNemar's test.Tests for line parallelism, relative potency and ED50 were based onleast squares regression in a program for pharmacological statistics.The data from the nonparametric rating scale was analyzed usingFriedman's analysis of variance model (ANOVA).

VI. Results

A. Summary of Xylazine-Induced Emesis Results in Felines.

As shown below in Table I, varying doses of R-(+)-DPAT and S-(−)-DPATwere administered to cats not susceptible to motion sickness.

TABLE I Compound % Mean Defensive Compound/ Dose Mean ProtectionDefensive Behavior Composition (mg/kg) Latency* (vomiting) Score Scalen= R/S-(+/−)-DPAT 0.16 0.0 100.00 2.0 Moderate 5 R-(+)-DPAT 0.02 0.00100.00 2.0 Moderate 5 R-(+)-DPAT 0.04 0.00 100.00 3.0 Strong 3R-(+)-DPAT 0.08 0.00 100.00 3.0 Strong 6 S-(−)-DPAT 0.08 1.58 75.00 0.0None 4 S-(−)-DPAT 0.16 0.82 85.71 0.0 None 7 S-(−)-DPAT 0.32 1.00 80.001.0 Slight 5 SALINE 0.00 5.06 0.00 0.0 None 7 R-(+)-DPAT + 0.02(R-(+)-DPAT)/ 0.74 83.33 1.0 Slight 6 S-(−)-DPAT 0.08 (S-(−)-DPAT)R-(+)-DPAT + 0.04 (R-(+)-DPAT)/ 5.00 75.00 2.0 Moderate 4 S-(−)-DPAT0.08 (S-(−)-DPAT) R-(+)-DPAT + 0.02 (R-(+)-DPAT)/ 0.00 100.00 0.6 None 5S-(−)-DPAT 0.16 (S-(−)-DPAT) R-(+)-DPAT + 0.04 (R-(+)-DPAT)/ 2.23 40.000.6 None 5 S-(−)-DPAT 0.16 (S-(−)-DPAT) *Latency is the mean latency toretch/vomit, in minutes.

Example 2: Blocking Cisplatin-Induced Emesis

Further experiments were performed as outlined in Example 1 above,except that the emesis-inducing agent used in the tests was cisplatin inplace of xylazine. The cats were injected subcutaneously with eithercis-platin or a sodium chloride vehicle. As shown below in Table II, an8:1 ratio of S-(−)-DPAT to R-(+)-DPAT was administered to cats.

The cats were observed and scored using the vomit scale and defensivescore described above.

TABLE II Mean % Mean Mean Mean Latency Protection Emetic DefensiveCompound Score (min) (vomiting) Events Score 0.02 mg/kg R(+)- 19 251.8040.00 2 none DPAT/0.16 mg/kg S(−)-DPAT 0.9% sodium chloride 27 62.200.00 8 none

Example 3: 5-HT_(1A) In-Vitro Analysis

A. Binding Affinity.

The percent inhibition of agonist response was recorded for severalmolar log concentrations of the compositions listed below in Table III.As represented graphically in FIG. 2, racemic (+/−)-8-OH-DPAT has a highbinding affinity for the 5-HT_(1A) receptor (Ki=0.62 nM) (Table III,FIG. 2). Likewise, R(+)-8-OH-DPAT and S(−)-8-OH-DPAT also have highbinding affinities for the 5-HT_(1A) receptor (Ki=0.62 nM and 0.5 nM,respectively) (Table III).

B. Cellular Functionality.

The percent of control agonist response was recorded for several logconcentrations of compounds/compositions. As shown in FIG. 3 and TableIII, racemic (+/−)-8-OH-DPAT is a potent agonist of the 5-HT_(1A)receptor (EC₅₀=0.62 nM). Likewise, R(+)-8-OH-DPAT and S(−)-8-OH-DPAT arealso potent agonists of the 5-HT_(1A) receptor (EC₅₀=0.81 nM and 0.35nM, respectively) (Table III, FIGS. 4 and 5). Contrary to previousfindings (Cornfield L. et al., 1991, Hadrava V. et al., 1996, DabrowskaJ. et al., 2006), both R(+)-8-OH-DPAT and S(−)-8-OH-DPAT are fullagonists of the 5-HT_(1A) receptor.

TABLE III 5-HT_(1A) Receptor Binding Affinity (Human Ligand). BindingCellular Function Cellular Function (Ki, nM) Agonist (EC₅₀, nM)Antagonist (IC₅₀, nM) (+/−)-8-OH- 5.5 0.36 Inactive DPAT R(+)-8-OH- 0.620.81, Full Agonist Inactive DPAT S(−)-8-OH- 0.5 0.35 Full AgonistInactive DPAT

Example 4: Blocking Motion-Induced and Chemically-Induced Emesis inShrews

The ability of the present OH-DPAT compositions to block emesis wasfurther tested in Asian house shrews (Suncus murinus) using both amotion-induced model of emesis and a chemically-induced model of emesis.

Motion-Induced Emesis

Animals for use in testing the present compounds in connection withmotion-induced emesis were included only if they vomited on both of twoconsecutive tests prior being treated with the test compound or vehicle.Male shrews were found to be more susceptible to emesis and were usedfor motion studies. In addition, test subjects received one test withsaline alone to test for conditioned vomiting. A repeated measuresdesign was employed. All tests were separated by one week to preventhabituation.

Motion sickness was induced by placing animals in individual holders(10×15×12 cm) mounted on a linear reciprocating shaker. Test subjectshad five minutes of acclimation followed by ten minutes of motion at 1Hz and 30 mm excursion. The latency for each emesis event and the numberof events was recorded for each shrew. The composition used in Example2, comprising an 8:1 ratio of S-(−)-DPAT to R-(+)-DPAT, was administeredsubcutaneously 15 minutes before motion was initiated in doses of 0.009mg/kg, 0.018 mg/kg, 0.036 mg/kg, and 0.08 mg/kg.

Each test was videotaped for scoring and then archived. The duration ofthe retch/vomit sequence for each test animal was roughly two seconds.Incidents of violent dorsoflexion with flexion/extension of thehindquarters were counted as indications of emesis with or without thepresence of vomitus. Tests with the stimulus alone were conducted at theend of the dose-response curve to verify that habituation had notoccurred.

The results of the foregoing tests are shown in FIG. 6. As can be seenin that figure, approximately 65% of the animals not treated with thetest compound experienced emesis, while the treated animals experiencedreduced or no emesis in a dose-dependent manner. Animals treated with0.036 and 0.08 mg/kg of the test compound experienced no emesis.

Drug Induced Emesis

Animals evaluated in the motion-induced emesis test described abovewhich did not evidence emesis as a result of motion, primarily femaleshrews, were assigned to be tested in a model of drug induced emesis.Shrews in this group received 10 mg/kg of nicotine tartaratesubcutaneously and were then monitored for 30 minutes. The number ofepisodes of emesis and the latency for each event were recorded. Thetest compound used in Example 2, comprising an 8:1 ratio of S-(−)-DPATto R-(+)-DPAT, was administered subcutaneously 15 minutes before thenicotine compound was administered. The doses of the test compoundadministered were 0.009 mg/kg, 0.018 mg/kg, 0.036 mg/kg, 0.058 mg/kg,and 0.08 mg/kg.

The only prodromal observation (indicating the onset of emesis) was theobservation of reduced motor activity before emesis. Animals wereobserved for retching and emetic responses for 90 minutes post-dosing.Tests were conducted at the end of the dose-response curve involvinginjecting saline alone in order to look for conditioned vomiting.

The results of the foregoing tests are shown in FIG. 7. As can be seenin that figure, all of the animals not treated with the test compound,i.e. treated only with nicotine tartarate, experienced emesis, while thetreated animals experienced reduced or no emesis in a dose-dependentmanner. Animals treated with 0.08 mg/kg of the test compound experiencedno emesis.

A group of shrews were also tested for emesis in response to theadministration of 20 mg/kg of cisplatin intraperitoneally using theprotocol described above, except that the test compound was administered30 minutes after cisplatin administration. The results are shown in FIG.8, which shows a reduction in emesis in the treated animals in adose-dependent manner, with animals receiving at least 0.36 mg/kg of thetest compound exhibiting a statistically significant reduction insymptoms of emesis.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments, other embodiments arepossible. The steps disclosed for the present methods, for example, arenot intended to be limiting nor are they intended to indicate that eachstep is necessarily essential to the method, but instead are exemplarysteps only. Therefore, the scope of the appended claims should not belimited to the description of preferred embodiments contained in thisdisclosure. All references cited herein are incorporated by reference intheir entirety.

What is claimed is:
 1. A composition comprising8-hydroxy-2-(dipropylamino)tetralin, wherein the ratio of the Senantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the Renantiomer of the 8-hydroxy-2-(dipropylamino)tetralin is between 2:1 and10:1.
 2. The composition of claim 1, wherein the ratio of the Senantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the Renantiomer of the 8-hydroxy-2-(dipropylamino)tetralin is between 4:1 and8:1.
 3. The composition of claim 1, wherein the ratio of the Senantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the Renantiomer of the 8-hydroxy-2-(dipropylamino)tetralin is 4:1.
 4. Thecomposition of claim 1, wherein the ratio of the S enantiomer of the8-hydroxy-2-(dipropylamino)tetralin to the R enantiomer of the8-hydroxy-2-(dipropylamino)tetralin is 8:1.
 5. The composition of claim1, wherein the composition further comprises pharmaceutically acceptableexcipients.
 6. A composition comprising8-hydroxy-2-(dipropylamino)tetralin, wherein the ratio of the Senantiomer of the 8-hydroxy-2-(dipropylamino)tetralin to the Renantiomer of the 8-hydroxy-2-(dipropylamino)tetralin is 8:1.
 7. Amethod for the treatment of emesis in a mammal, comprising the step ofadministering to the mammal a composition comprisingS(−)-8-hydroxy-2-(dipropylamino)tetralin andR(+)-8-hydroxy-2-(dipropylamino)tetralin, wherein the ratio of theS(−)-8-hydroxy-2-(dipropylamino)tetralin toR(+)-8-hydroxy-2-(dipropylamino)tetralin is between 2:1 and 10:1.
 8. Themethod of claim 7, wherein the ratio of theS(−)-8-hydroxy-2-(dipropylamino)tetralin toR(+)-8-hydroxy-2-(dipropylamino)tetralin is 2:1.
 9. The method of claim7, wherein the ratio of the S(−)-8-hydroxy-2-(dipropylamino)tetralin toR(+)-8-hydroxy-2-(dipropylamino)tetralin is 4:1.
 10. The method of claim7, wherein the ratio of the S(−)-8-hydroxy-2-(dipropylamino)tetralin toR(+)-8-hydroxy-2-(dipropylamino)tetralin is 10:1.
 11. The method ofclaim 7, wherein the emesis is anticipatory emesis.
 12. The method ofclaim 7, wherein the emesis is delayed emesis.
 13. The method of claim7, the mammal is a human.
 14. The method of claim 7, wherein the amountof S(−)-8-Hydroxy-2-(dipropylamino)tetralin administered is between 0.08mg/kg and 0.16 mg/kg.
 15. The method of claim 14, wherein the amount ofS(−)-8-Hydroxy-2-(dipropylamino)tetralin administered is 0.08 mg/kg. 16.The method of claim 7, wherein the amount ofR(+)-8-Hydroxy-2-(dipropylamino)tetralin administered is between 0.02mg/kg and 0.04 mg/kg.